Manifold medicine: A schema that expands treatment dimensionality.

Drug discovery currently focuses on identifying new druggable targets and drug repurposing. Here, we illustrate a third domain of drug discovery: the dimensionality of treatment regimens. We formulate a new schema called 'Manifold Medicine', in which disease states are described by vectorial positions on several body-wide axes. Thus, pathological states are represented by multidimensional 'vectors' that traverse the body-wide axes. We then delineate the manifold nature of drug action to provide a strategy for designing manifold drug cocktails by design using state-of-the-art biomedical and technological innovations. Manifold Medicine offers a roadmap for translating knowledge gained from next-generation technologies into individualized clinical practice.

Sex-tailored pharmacology and COVID-19: Next steps towards appropriateness and health equity.

Making gender bias visible allows to fill the gaps in knowledge and understand health records and risks of women and men. The coronavirus disease 2019 (COVID-19) pandemic has shown a clear gender difference in health outcomes. The more severe symptoms and higher mortality in men as compared to women are likely due to sex and age differences in immune responses. Age-associated decline in sex steroid hormone levels may mediate proinflammatory reactions in older adults, thereby increasing their risk of adverse outcomes, whereas sex hormones and/or sex hormone receptor modulators may attenuate the inflammatory response and provide benefit to COVID-19 patients. While multiple pharmacological options including anticoagulants, glucocorticoids, antivirals, anti-inflammatory agents and traditional Chinese medicine preparations have been tested to treat COVID-19 patients with varied levels of evidence in terms of efficacy and safety, information on sex-targeted treatment strategies is currently limited. Women may have more benefit from COVID-19 vaccines than men, despite the occurrence of more frequent adverse effects, and long-term safety data with newly developed vectors are eagerly awaited. The prevalent inclusion of men in randomized clinical trials (RCTs) with subsequent extrapolation of results to women needs to be addressed, as reinforcing sex-neutral claims into COVID-19 research may insidiously lead to increased inequities in health care. The huge worldwide effort with over 3000 ongoing RCTs of pharmacological agents should focus on improving knowledge on sex, gender and age as pillars of individual variation in drug responses and enforce appropriateness.

Clinical Pharmacology Regulatory Sciences in Drug Development and Precision Medicine: Current Status and Emerging Trends.

In the regulatory setting, clinical pharmacology focuses on the impact of intrinsic and extrinsic factors on inter-patient and intra-subject variability in drug exposure and response. This translational science contributes to the understanding of the benefit-risk profile in individual patients and the development of relevant therapeutic monitoring and management strategies. Clinical pharmacology also plays a major role in the development and qualification of drug development tools. This article presented some recent examples to illustrate the important roles of clinical pharmacology in drug development and evaluation. In addition, emerging trends in clinical pharmacology regulatory sciences were also discussed, including the Model-Informed Drug Development (MIDD) pilot program, the use of real-world data to generate real-world evidence, and leveraging advances in basic, biomedical, and clinical science into useful tools for drug development and evaluation. Continued advances in clinical pharmacology can be the basis of more rational and efficient drug development and improved access to new drug treatments that are tailored to the patient to achieve better efficacy and safety.

A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2020.

While the COVID-19 pandemic also affected the work of regulatory authorities, the US Food and Drug Administration approved a total of 53 new drugs in 2020, one of the highest numbers in the past decades. Most newly approved drugs related to oncology (34%) and neurology (15%). We discuss these new drugs by level of innovation they provide, i.e., first to treat a condition, first using a novel mechanisms of action, and "others." Six drugs were first in indication, 15 first using a novel mechanism of action, and 32 other. This includes many drugs for the treatment of orphan indications and some for the treatment of tropical diseases previously neglected for commercial reasons. Small molecules continue to dominate new drug approvals, followed by antibodies. Of note, newly approved drugs also included small-interfering RNAs and antisense oligonucleotides. These data show that the trend for declines in drug discovery and development has clearly been broken.

Evolving drug regulatory landscape in China: A clinical pharmacology perspective.

In order to encourage innovative medicine to address Chinese unmet medical needs, China has changed its drug regulatory landscape to speed up access to new medicines. In order to understand the fast-changing landscape and to enable planning of more global drug development programs and study designs in China, we reviewed 15 published clinical pharmacology-related guidances by the National Medical Products Administration (NMPA), and compared them with reference guidances from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the International Conference on Harmonization (ICH), to understand the similarities and differences, especially any China-specific requirements, such as ethnic sensitivity analysis. Overall, by reviewing these clinical pharmacology-related NMPA guidances, it is clear that NMPA guidances are very similar to FDA, EMA, and ICH guidances. There are no relevant differences in the major principles, but some differences in structure, contents, and focus were noted. The NMPA is adapting flexibility statements into newly published guidances. Ethnic sensitivity analysis needs to be implemented early in drug development plans. The NMPA encourages sponsors to conduct early clinical trials in China or include China early in multiregional clinical trials, and to obtain safety, efficacy, and pharmacokinetic data for ethnic sensitivity analysis. Depending on the stage of development, ethnic sensitivity analysis can be conducted using in vitro or literature data, other Asian clinical data, or Chinese clinical data.

Future avenues for Alzheimer's disease detection and therapy: liquid biopsy, intracellular signaling modulation, systems pharmacology drug discovery.

When Alzheimer's disease (AD) disease-modifying therapies will be available, global healthcare systems will be challenged by a large-scale demand for clinical and biological screening. Validation and qualification of globally accessible, minimally-invasive, and time-, cost-saving blood-based biomarkers need to be advanced. Novel pathophysiological mechanisms (and related candidate biomarkers) - including neuroinflammation pathways (TREM2 and YKL-40), axonal degeneration (neurofilament light chain protein), synaptic dysfunction (neurogranin, synaptotagmin, α-synuclein, and SNAP-25) - may be integrated into an expanding pathophysiological and biomarker matrix and, ultimately, integrated into a comprehensive blood-based liquid biopsy, aligned with the evolving ATN + classification system and the precision medicine paradigm. Liquid biopsy-based diagnostic and therapeutic algorithms are increasingly employed in Oncology disease-modifying therapies and medical practice, showing an enormous potential for AD and other brain diseases as well. For AD and other neurodegenerative diseases, newly identified aberrant molecular pathways have been identified as suitable therapeutic targets and are currently investigated by academia/industry-led R&D programs, including the nerve-growth factor pathway in basal forebrain cholinergic neurons, the sigma1 receptor, and the GTPases of the Rho family. Evidence for a clinical long-term effect on cognitive function and brain health span of cholinergic compounds, drug candidates for repositioning programs, and non-pharmacological multidomain interventions (nutrition, cognitive training, and physical activity) is developing as well. Ultimately, novel pharmacological paradigms, such as quantitative systems pharmacology-based integrative/explorative approaches, are gaining momentum to optimize drug discovery and accomplish effective pathway-based strategies for precision medicine. This article is part of the special issue on 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.

An Introduction to Machine Learning.

In the last few years, machine learning (ML) and artificial intelligence have seen a new wave of publicity fueled by the huge and ever-increasing amount of data and computational power as well as the discovery of improved learning algorithms. However, the idea of a computer learning some abstract concept from data and applying them to yet unseen situations is not new and has been around at least since the 1950s. Many of these basic principles are very familiar to the pharmacometrics and clinical pharmacology community. In this paper, we want to introduce the foundational ideas of ML to this community such that readers obtain the essential tools they need to understand publications on the topic. Although we will not go into the very details and theoretical background, we aim to point readers to relevant literature and put applications of ML in molecular biology as well as the fields of pharmacometrics and clinical pharmacology into perspective.

Will Artificial Intelligence for Drug Discovery Impact Clinical Pharmacology?

As the field of artificial intelligence and machine learning (AI/ML) for drug discovery is rapidly advancing, we address the question "What is the impact of recent AI/ML trends in the area of Clinical Pharmacology?" We address difficulties and AI/ML developments for target identification, their use in generative chemistry for small molecule drug discovery, and the potential role of AI/ML in clinical trial outcome evaluation. We briefly discuss current trends in the use of AI/ML in health care and the impact of AI/ML context of the daily practice of clinical pharmacologists.

WHO guide to good prescribing is 25 years old: quo vadis?

INTRODUCTION: Twenty-five years ago, the World Health Organization (WHO) published the Guide to Good Prescribing (GGP), followed by the accompanying Teacher's Guide to Good Prescribing (TGGP). The GGP is based on a normative 6-step model for therapeutic reasoning and prescribing, and provides a six-step guide for students to the process of rational prescribing. METHOD: We reviewed the need to update both WHO publications by evaluating their use and impact, including new (theoretical) insights and demands. Based on information from literature, Internet, and other (personal) sources, we draw the following conclusions. RESULTS: 1. An update of the GGP and TGGP, both in terms of content and form, is necessary because of the current need for these tools (irrational medicine use and unavailability of medicines), the lack of similar documents, and the lack of connection with recent developments, such as Internet and modern education; 2. The basic (6-step) model of the GGP is effective in terms of rational prescribing in the undergraduate situation and is still consistent with current theories about (context) learning, clinical decision-making, and clinical practice; 3. The dissemination and introduction of the GGP and TGGP in education has been successful so far, but is still not optimal because of lack of support and cooperation. CONCLUSIONS: On the basis of the evaluation results, a plan for the revision of the GGP and TGGP is presented.

Digoxin as a glycosylated steroid-like therapeutic drug: Recent advances in the clinical pharmacology and bioassays of pharmaceutical compounds.

Digoxin is cardiac glycosylated steroid like drug which is the fifth most commonly prescribed in US. Since the health of human population is largely determined by pharmacy they utilized, toxicity and side effects of pharmaceutics can put the safety of people in jeopardy and lead to some devastating impacts. Therefore, it is essential to detect and monitor small molecules like digoxin more meticulously. Although digoxin has positive inotropic and batmotropic impact on heart muscle, it has also negative chronotropic and dromotropic effect. The prescription dose of this drug is 1-2 ng/ml and more than 2.8 ng/ml of this medication cause toxicity. Hence, there is small variation between therapeutic and toxic dosage of digoxin. Abundant conventional methods have been introduced for digoxin monitoring such Liquid chromatography (LC), LC-MS, HPLC. However, they suffer expensive equipment, long lasting procedure and high limit of detection. Hence, various advance immunosorbent, biosensors and aptasensors have been introduced. The purpose of this review is limited to pointing convention methods drawbacks and introducing novel digoxin enzyme-linked or non-enzymatic immunosorbent assays, and biosensors paying special attention to their basic strategies and detection abilities. Future trends in Bio and immune sensors used for onset monitoring and detection of digoxin are also highlighted.

Pharmacometrics and Systems Pharmacology 2030.

In 2012, a new journal was launched from the ASCPT family, CPT: Pharmacometrics and Systems Pharmacology (PSP) as both quantitative system pharmacology (QSP) and pharmacometrics were growing fields in pharmacology, drug development, and drug use. In this Perspective, the present editors and associate editors of PSP want to share their strategic vision of where these two fields, separately and together, should, would, or could be 10 years from now.

The Future of Precision Medicine.

Precision medicine is an emerging framework to maximize therapeutic benefit by modifying the treatment for individual patients based on their variations in demographic, genomic, and environmental factors. In particular, "Pharmacogenomics" and "Therapeutic Drug Monitoring" are key elements of individualized drug treatment, staging Clinical Pharmacology at the forefront of precision medicine.